Parkinson's Disease
Conditions
Keywords
neurodegeneration, gold, nanocrystal, NAD+, redox, 31P-MRS, Parkinson's Disease, magnetic resonance spectroscopy, nanoparticle, nanomedicine, NADH
Brief summary
REPAIR-PD is a single-center open label pilot, sequential group, investigator and patient blinded study to assess the CNS metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who have been diagnosed with Parkinson's Disease (PD) within three (3) years of Screening. The primary endpoint is the ratio of the oxidized to reduced form of nicotinamide adenine dinucleotide (NAD+:NADH) measured non-invasively by 31phosphorous magnetic resonance spectroscopy (31P-MRS).
Detailed description
This is a single-center open label pilot, sequential group, investigator blinded study of the CNS metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who have been diagnosed with Parkinson's Disease within three years of Screening. The Sponsor will select a starting treatment dose of CNM-Au8 for the initial treatment. Investigators and patients will be blinded to each cohort's study dose. Upon completion of the first treatment cohort, the Sponsor will select a single dose or two different doses for the subsequent second cohort from a pre-specified dosing selection plan based on the evaluation of the 31P-Magnetic Resonance Spectroscopy (31P-MRS) changes versus baseline in the first cohort. Up to a total of two treatment cohorts may be studied (n=15 patients/cohort, total n=30 patients). All patients will receive daily oral treatment over twelve consecutive weeks during each cohort's Treatment Period. There will be three study periods per treatment cohort: 1. A six-week screening period (Screening Period); 2. A twelve-week treatment period (Treatment Period); 3. A four-week follow-up period (End-of-Study Assessment). The primary study outcome, CNS metabolic changes, will be assessed based upon each patient's Week 12 study visit versus the pre-treatment baseline. The primary endpoint is the brain metabolic effects of treatment with CNM-Au8 as assessed by an improvement of 31P-MRS assessment of Brain Tissue Cellular Redox Potential defined by the measured tissue ratio of NAD+:NADH concentrations following 12 weeks of once daily treatment.
Interventions
CNM-Au8 is a dark red/purple-colored liquid formulation consisting of a stable suspension of faceted clean surfaced elemental gold nanocrystals in buffered deionized water with a concentration of up to 0.5 mg/mL of gold. The formulation is buffered by sodium bicarbonate present at a concentration of 0.546 mg/mL. There are no other excipients. The drug product is formulated to be taken orally and will be provided in single dose HDPE containers. The study doses vary by the concentration of gold nanocrystals per milliliter in a volume of 60 mL.
Sponsors
University of Texas Southwestern Medical Center
Clene Nanomedicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Research participants and site personnel are not masked to study drug, but will be blinded to study dose for each cohort (single-blinded).
Intervention model description
Open Label, Investigator Blinded, Sequential Cohort (max of 2 cohorts amongst the possible 4 interventions)
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Able to understand and give written informed consent and follow study procedures. 2. Male or female, aged 30 - 80 years or age (inclusive) at the time of PD diagnosis. 3. PD subjects will be recruited in accordance with the MDS Clinical Diagnostic Criteria for PD: 1. Parkinsonism present (bradykinesia + either rest tremor or rigidity) 2. 2 of the following 4 supportive criteria: i. Clear and dramatic beneficial response to dopaminergic medication ii. Presence of levodopa-induced dyskinesias iii. Rest tremor of a limb iv. Olfactory loss or cardiac sympathetic denervation seen on prior MIBG SPECT 4. Duration of PD since diagnosis is \</= 3 years (inclusive) 5. Modified Hoehn and Yahr stage \</= 3 6. Treatment with dopaminergic therapy for at least 12-weeks and with no change in current medications within the prior 6-weeks
Exclusion criteria
1. Atypical parkinsonism, including that due to drugs, metabolic disorders, encephalitis, cerebrovascular disease, normal pressure hydrocephalus, or other neurodegenerative disease. 2. The presence of any of the following: 1. Unequivocal cerebellar abnormalities 2. Downward vertical gaze limitation or slowing of downward saccades 3. Diagnosis of behavioral variant frontotemporal dementia or primary progressive aphasia 4. Parkinsonian features restricted to the lower limbs for \> 3 years 5. Treatment with dopamine blockers or depleters in a time course consistent with drug-induced parkinsonism 6. Absence of an observable response to high dose levodopa despite moderate disease severity 7. Expert considers a diagnosis of alternative syndrome more likely than PD 8. Rapid progression of gait impairment requiring wheelchair within 5 years of onset 9. Complete absence of progression of motor symptoms over 3 years unless due to treatment 10. Early bulbar dysfunction within the first 5 years since diagnosis 11. Inspiratory respiratory dysfunction (stridor or frequent sighs) 12. Severe autonomic failure in the first 5 years 13. Recurrent falls (\>1 per year) because of impaired balance in the first 3 years 14. Disproportionate dystonic anterocollis or hand contractures of hands or feet within 10 years 15. Absence of any of the common non-motor features of PD despite 5 years of disease 16. Otherwise unexplained pyramidal tract signs (weakness, hyperreflexia, or extensor toe signs) 17. Bilateral symmetric parkinsonism 3. Mini-Mental State Exammination (MMSE) score of less than 19. 4. Patient with a history of any clinically significant or unstable medical condition based on the Investigator's judgment. 5. History of human immunodeficiency virus (HIV), hepatitis C (HepC) virus antibody, or hepatitis B (HepB) virus antibody. 6. Based on the investigator's judgment, patients who may have difficulty complying with the protocol and/or study procedures. 7. Patient with clinically significant abnormalities in hematology, blood chemistry, ECG, or physical examination not resolved by the Baseline visit which according to Investigator may interfere with study participation. 8. Patients with clinically significant hepatic or renal dysfunction or clinical laboratory findings that would limit the interpretability of change in liver or kidney function, or those with low platelet counts (\<150 x 109 per liter) or eosinophilia (absolute eosinophil count of ≥500 eosinophils per microliter) at Screening. 9. Patient participating in any other investigational drug trial or using investigational drug (within 12 weeks prior to screening and thereafter) 10. Positive screen for drugs of abuse or known history of alcohol abuse. 11. Women of child-bearing potential, or men, who are unwilling or unable to use accepted methods of birth control for up to 6 months following study participation. 12. Women with a positive pregnancy test, are lactating, or are planning to become pregnant during the study or within 6 months of the end of this trial. 13. Patients with implanted metal objects in their body that may be affected by an MRI procedure. 14. Patients who are claustrophobic or otherwise unlikely to be able to complete the MRI scanning procedures. 15. History of allergy to gold in any form. 16. Patient is considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 31P-MRS Redox Ratio | Baseline to 12 Weeks | The change in 31P-MRS NAD+/NADH ratio was measured by a partial volume coil that images the parietal and occipital lobes as a single value with respect to the fraction (%) of the nicotinamide adenine dinucleotide (NAD) signal measured as either the oxidized (NAD+) or reduced form (NADH). The primary endpoint was the mean change from Baseline to Week 12 in the ratio of NAD+ to NADH (NAD+/NADH) in the Intent to Treat population. A paired t-test was used to analyze the mean change from baseline. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NAD+ | At 12 Week | Mean change in average CNS concentration of NAD+ \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Pooled NAD+/NADH | At 12 Weeks | Mean change in average CNS concentration of pooled NAD+/NADH \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of ATP | At 12 Week | Mean change in average CNS concentration of ATP \[mmol/kg\] (as internal reference) by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Phosphocreatine (PCr) | At 12 Week | Mean change in average CNS concentration of PCr \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Intracellular Inorganic Phosphate (Pi(in)) | At 12 Week | Mean change in average CNS concentration of Pi(in) \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Extracellular Inorganic Phosphate (Pi(ex)) | At 12 Week | Mean change in average CNS concentration of Pi(ex) \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Uridine Diphosphate Glucose (UDPG) | At 12 Week | Mean change in average CNS concentration of UDPG \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Membrane Component Tissue Concentration of Phosphoethanolamine (PE) | At 12 Weeks | Mean change in average CNS concentration of PE \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NADH | At 12 Week | Mean change in average CNS concentration of NADH \[% Fraction\] by treatment group |
| Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerolphophoethanolamine (GPE) | At 12 Weeks | Mean change in average CNS concentration of GPE \[mmol/kg\] by treatment group |
| Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerophosphocholine (GPC) | At 12 Weeks | Mean change in average CNS concentration of GPC \[mmol/kg\] by treatment group |
| Measures of Gait | at 12 weeks | Measured by APDM instrumented Timed up and go test. |
| Measures of Balance | at 12 weeks | Measured by APDM Instrumented Postural Sway Test |
| Measure of Mobility | at 12 weeks | Measured by APDM instrumented Walk Test |
| Measurements of Global Impression of Disease Improvement | at 12 weeks | Using Clinician Global Impression Scale. Scale is rated from 1-7, with 1 representing Very much improved and 7 representing very much worse. |
| Measurements of Global Impression of Disease Severity | at 12 weeks | Using Patient Global Impression Scale. Scale is rated from 1-7, with 1 representing very mush improved, and 7 representing very much worse. |
| Measurements of Disease Progression | at 12 weeks | Using Unified Parkinson's Disease Rating Scale. The scale is based off of participants symptoms, with a lower value representing a being closer to no impairments. |
| Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Phosphocholine (PC) | At 12 Weeks | Mean change in average CNS concentration of PC \[mmol/kg\] by treatment group |
Countries
United States
Participant flow
Recruitment details
The study was a single-center open-label pilot, sequential group, investigator-blinded study of the CNS metabolic effects, safety, pharmacokinetics, and pharmacodynamics of CNM-Au8 in patients who had been diagnosed with Parkinson's Disease (PD) within three (3) years of Screening. Patients were screened over a 6-week period. Patients who met the inclusion criteria and none of the exclusion criteria were enrolled into the clinical study.
Pre-assignment details
There was no washout or run-in period that occurred between ICF signing and IP initiation. Once the participant signed the ICF and was confirmed to be eligible for the study, they were randomized into the study and dosed with IP.
Participants by arm
| Arm | Count |
|---|---|
| Active: 30mg CNM-Au8 All participants in this group were dosed with 30 mg CNM-Au8 once daily.
CNM-Au8 is an aqueous suspension of clean surfaced faceted nanocrystals consisting of gold atoms self-organized into various geometrical shapes (hexagonal bi-pyramid, pentagonal bi-pyramid, tetrahedron, decahedron, planar spheroids). These highly pure gold nanocrystals are suspended in purified water buffered with sodium bicarbonate (NaHCO3) nominally concentrated to 0.25 mg/L (250 ppm) to achieve a 30 mg dose CNM-Au8.
CNM-Au8 was administered orally in a total volume of 120 mL taken once daily from two single-unit sterile 60 mL HDPE containers. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Active: 30mg CNM-Au8 |
|---|---|
| Age, Continuous | 65.7 years STANDARD_DEVIATION 7.6 |
| BMI | 25.3 kg/m^2 STANDARD_DEVIATION 4.67 |
| Child bearing potential | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 172.6 cm STANDARD_DEVIATION 10.85 |
| MMSE Score | 28.8 Score STANDARD_DEVIATION 1.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
| Weight | 75.6 kg STANDARD_DEVIATION 16.63 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 6 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
31P-MRS Redox Ratio
The change in 31P-MRS NAD+/NADH ratio was measured by a partial volume coil that images the parietal and occipital lobes as a single value with respect to the fraction (%) of the nicotinamide adenine dinucleotide (NAD) signal measured as either the oxidized (NAD+) or reduced form (NADH). The primary endpoint was the mean change from Baseline to Week 12 in the ratio of NAD+ to NADH (NAD+/NADH) in the Intent to Treat population. A paired t-test was used to analyze the mean change from baseline.
Time frame: Baseline to 12 Weeks
Population: Intent to Treat Population (ITT):~The Intent to Treat population consisted of all screened subjects who were assigned a treatment assignment number.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active: 30mg CNM-Au8 | 31P-MRS Redox Ratio | 0.3856 Change in 31P-MRS Redox Ratio | Standard Deviation 0.79968 |
Comparison: The primary efficacy endpoint is the mean change in the average NAD+/NADH brain ratio from baseline to Week 12 using a partial volume coil 31P-MRS data on the Per Protocol Treatment Population. A paired t-test will be used to analyze the mean change from baseline.p-value: 0.1077t-test, 2 sided
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of ATP
Mean change in average CNS concentration of ATP \[mmol/kg\] (as internal reference) by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Extracellular Inorganic Phosphate (Pi(ex))
Mean change in average CNS concentration of Pi(ex) \[mmol/kg\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Intracellular Inorganic Phosphate (Pi(in))
Mean change in average CNS concentration of Pi(in) \[mmol/kg\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NAD+
Mean change in average CNS concentration of NAD+ \[mmol/kg\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of NADH
Mean change in average CNS concentration of NADH \[% Fraction\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Phosphocreatine (PCr)
Mean change in average CNS concentration of PCr \[mmol/kg\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Pooled NAD+/NADH
Mean change in average CNS concentration of pooled NAD+/NADH \[mmol/kg\] by treatment group
Time frame: At 12 Weeks
Other Pre-specified
Mean Change in 31P-MRS Bioenergetic Metabolite CNS Tissue Concentration of Uridine Diphosphate Glucose (UDPG)
Mean change in average CNS concentration of UDPG \[mmol/kg\] by treatment group
Time frame: At 12 Week
Other Pre-specified
Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerolphophoethanolamine (GPE)
Mean change in average CNS concentration of GPE \[mmol/kg\] by treatment group
Time frame: At 12 Weeks
Other Pre-specified
Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Glycerophosphocholine (GPC)
Mean change in average CNS concentration of GPC \[mmol/kg\] by treatment group
Time frame: At 12 Weeks
Other Pre-specified
Mean Change in 31P-MRS Membrane Component CNS Tissue Concentration of Phosphocholine (PC)
Mean change in average CNS concentration of PC \[mmol/kg\] by treatment group
Time frame: At 12 Weeks
Other Pre-specified
Mean Change in 31P-MRS Membrane Component Tissue Concentration of Phosphoethanolamine (PE)
Mean change in average CNS concentration of PE \[mmol/kg\] by treatment group
Time frame: At 12 Weeks
Other Pre-specified
Measurements of Disease Progression
Using Unified Parkinson's Disease Rating Scale. The scale is based off of participants symptoms, with a lower value representing a being closer to no impairments.
Time frame: at 12 weeks
Other Pre-specified
Measurements of Global Impression of Disease Improvement
Using Clinician Global Impression Scale. Scale is rated from 1-7, with 1 representing Very much improved and 7 representing very much worse.
Time frame: at 12 weeks
Other Pre-specified
Measurements of Global Impression of Disease Severity
Using Patient Global Impression Scale. Scale is rated from 1-7, with 1 representing very mush improved, and 7 representing very much worse.
Time frame: at 12 weeks
Other Pre-specified
Measure of Mobility
Measured by APDM instrumented Walk Test
Time frame: at 12 weeks
Other Pre-specified
Measures of Balance
Measured by APDM Instrumented Postural Sway Test
Time frame: at 12 weeks
Other Pre-specified
Measures of Gait
Measured by APDM instrumented Timed up and go test.
Time frame: at 12 weeks